Brain-Behavior and Genetic Studies of the 22q11DS is a collaborative RO1 between Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). The collaboration combines genetic and neurobiologic paradigms to advance understanding of the pathogenesis of schizophrenia (SCZ). CHOP has established the largest available sample of over 800 patients with 22q11DS who have been well characterized by genetics and genomics. There is a substantial risk for developing SCZ in adolescents and young adults with 22q11DS (23-30%), with illness presentation and course similar to SCZ in the general population (1%). Penn has extensive experience in brain-behavior studies in SCZ including phenotypic characterization, computerized neurocognitive testing, and neuroimaging measures that provide complementary quantitative phenotypes. The goal of the collaboration is to capitalize on this unique sample of 22q11DS and obtain neuropsychiatric, neurocognitive, and neuroimaging phenotypes of brain structure and function. The design will include age- stratified measures of brain structure with Magnetic Resonance Imaging (MRI) using volume-based morphometry, and connectivity with Diffusion Tensor Imaging (DTI). Functional MRI (fMRI) studies will examine brain circuitry activated in response to neurobehavioral probes (Specific Aim 1). The neuropsychiatric, neurobehavioral and neuroimaging phenotypes in 22q11DS will be compared to patients with SCZ, those at clinical and genetic risk for SCZ, and cardiac and healthy controls. These groups are needed to establish the profile of phenotypic features and quantitative brain-behavior measures and their interactions (Specific Aim 2). To establish genetic mechanisms producing the neuropsychiatric, neurobehavioral and neuroimaging phenotypes, association with common SNPs will be examined using a genome-wide approach and selected candidate genes. Associations of copy number variants (CNVs) with SCZ quantitative phenotypes will be tested in 22q11DS samples both across the genome and within the 22q11DS region. Deep next generation sequencing on the "non-deleted" allele will be performed for genes in the 22q11DS region and selected candidate genes in patients with the deletion to determine whether specific mutations or alleles are associated with extreme values of SCZ related endophenotypes in 22q11DS individuals (Specific Aim 3). Specimens will be sent to the NIMH repository for transformation and DNA extraction. Data collection and quality control will be maintained and verified data will be regularly uploaded to the NIMH repository (Specific Aim 4). The proposed project will be the first of its kind to take a common deletion associated with SCZ and elucidate its behavioral, neurobiological and genetic substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11DS, the results will help identify pathways leading to SCZ in the general population in a way that will point to novel treatments. PUBLIC HEALTH RELEVANCE: Schizophrenia (SCZ) is a complex brain disorder with genetic substrates. It often emerges in adolescence and early adulthood with devastating effects. Of individuals with 22q11DS, 23-30% develops the SCZ phenotype, providing a unique opportunity to probe the pathogenesis of SCZ. Integration of genomics and neurobiology is key to understanding the causes of deficits, leading to early detection and advancing novel treatments.